Insulin Resistance (IR) is associated with vascular dysfunction and strokes. However, effects on the cerebral circulaton are completely unexplored. Our findings from isolated peripheral and cerebral arteries from IR rats have lead to the following hypothesis: IR impairs normal vascular dilator mechanisms in the cerebral circulaton and thereby exacerbates the potential for neurological damage due to stroke. We have created 3 specific aims: Specific Aim 1. Examination of effects of IR on responsiveness to dilator stimuli in isolated cerebral arteries. We will: First, examine effects of IR on endothelium-dependent dilator properties using pharmacological probes; Second, examine effects of IR on vascular smooth muscle function; Third, determine the effects of IR on arterial responsiveness to physiological stimuli; Fourth, determine whether restoration of normal cerebral vascular function is present after cessation of fructose feeding. Specific Aim 2. Elucidation of mechanisms of deranged cerebrovascular control mechanisms in IR. We will: First, examine the contributions of endothelium-derived factors to arterial dilation to pharmacological and physiological stimuli; Second, examine whether IR affects the vascular metabolism of arachidonic acid and L-arginine; Third, determine whether IR affects arterial responses to arachidonic acid or L-arginine metabolites; Fourth, examine effects of IR on vascular smooth muscle ATP-sensitive or calcium-activated potassium channels; Fifth, determine whether pharmacological augmentation of an endothelial-mediated dilator system restores normal vascular function in IR rats. Specific Aim 3. Examination of effects of IR on extent of neurological injury following experimental strokes. We will: First, examine effects of IR on brain injury after experimental strokes; Second, determine the role of impaired cerebral vascular dilator capacity in mediating enhanced infarct volume after stroke in IR animals; Third, determine whether cessation of fructose feeding improves outcome after stroke; Fourth, determine whether pharmacological augmentation of an endothelial-mediated dilator system protects against stroke in IR rats; Fifth, assess the ability of novel scavengers of oxygen free radicals to lessen neurological injury to stroke in IR rats. We believe that our studies will result in new and important findings that will lead to improved therapies to reduce morbidity and mortality in IR individuals.